title: Neuroprotection through excitability and mTOR required in ALS motoneurons to delay disease and extend survival.
abstract: Delaying clinical disease onset would greatly reduce neurodegenerative disease burden, but the mechanisms influencing early preclinical progression are poorly understood. Here, we show that in mouse models of familial motoneuron (MN) disease, SOD1 mutants specifically render vulnerable MNs dependent on endogenous neuroprotection signaling involving excitability and mammalian target of rapamycin (mTOR). The most vulnerable low-excitability FF MNs already exhibited evidence of pathology and endogenous neuroprotection recruitment early postnatally. Enhancing MN excitability promoted MN neuroprotection and reversed misfolded SOD1 (misfSOD1) accumulation and MN pathology, whereas reducing MN excitability augmented misfSOD1 accumulation and accelerated disease. Inhibiting metabotropic cholinergic signaling onto MNs reduced ER stress, but enhanced misfSOD1 accumulation and prevented mTOR activation in alpha-MNs. Modulating excitability and/or alpha-MN mTOR activity had comparable effects on the progression rates of motor dysfunction, denervation, and death. Therefore, excitability and mTOR are key endogenous neuroprotection mechanisms in motoneurons to counteract clinically important disease progression in ALS.
authors.affiliation: Friedrich Miescher Institut, Maulbeerstrasse 66, CH-4058 Basel, Switzerland; Institute of Cell Biology, University of Bern, Balzerstrasse 4, CH-3012 Bern, Switzerland.
authors.forename: Smita
authors.initials: S
authors.lastname: Saxena
authors.forename: Francesco
authors.initials: F
authors.lastname: Roselli
authors.forename: Katyayani
authors.initials: K
authors.lastname: Singh
authors.forename: Kerstin
authors.initials: K
authors.lastname: Leptien
authors.forename: Jean-Pierre
authors.initials: JP
authors.lastname: Julien
authors.forename: Francois
authors.initials: F
authors.lastname: Gros-Louis
authors.forename: Pico
authors.initials: P
authors.lastname: Caroni
mesh_terms: D000690:Amyotrophic Lateral Sclerosis / Q000139:chemically induced / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D000818:Animals; D001921:Brain / Q000378:metabolism / Q000473:pathology; D002470:Cell Survival / Q000235:genetics; D004195:Disease Models, Animal; D008297:Male; D051379:Mice; D008822:Mice, Transgenic; D009046:Motor Neurons / Q000378:metabolism* / Q000473:pathology; D009154:Mutation / Q000235:genetics; D015398:Signal Transduction / Q000502:physiology; D013482:Superoxide Dismutase / Q000378:metabolism*; D000072105:Superoxide Dismutase-1; D058570:TOR Serine-Threonine Kinases / Q000378:metabolism*
chemical_list: C000606291:Sod1 protein, mouse; D013482:Superoxide Dismutase; D000072105:Superoxide Dismutase-1; C546843:mTOR protein, mouse; D058570:TOR Serine-Threonine Kinases